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Antiallergic and antitussive drugs
F.A. Nelemans
17
Antiallergic and antitussive drugs
Editorial note Several drugs used in bronchial asthma and cough are dealt with in other chapters. These include xanthine compounds (Chapter 1), the opiates (Chapter 8), sympathomimetic and parasympatholytic agents (Chapter 14), the antihistamines (Chapter 16) and the corticosteroids (Chapter 41).
mean duration of treatment was 8 days and the dosage 2 tablets a day. Clinically, fenspiride was positively appreciated by 9 out of 10 patients. The number of side effects was small and they were not very specific (gastrointestinal, neurovegetative). Less than 10~ of the patients had side effects (3 c)
Ketotifen (Zaditen) (SED-IO, 292; SEDA-8, 171; SEDA-9, 155) DRUGS USED IN B R O N C H I A L ASTHMA
Cromolyn sodium (disodium cromoglieate) (SED-IO, 291; SEDA-8, 170; SEDA-9, 155) The illogical combination of cromolyn sodium with reproterol (SEDA-9, 155) was investigated in a further open multicenter study, now in 1872 patients. Increasing the number of patients does not improve a'basically invalid experiment. Here, too, the patients were pleased with the therapy and the, number of side effects was very small (l c). Since from the start the powdered form of cromoglicate has caused bronchial irritation in very occasional patients, it is interesting to observe the work done with a nebulizer solution. A 1% nebulizer solution (20 mg cromolyn sodium dissolved in 2.5 ml distilled water and nebulized over a 15-min period) has the same therapeutic effect and low incidence of side effects as the substance given by the use of the Spinhaler (20.
Fens#ride (Pneumorel 80) (SED-IO, 296) The efficacy and safety of fenspiride (which has bronchodilator and anti-inflammatory properties) has been studied in 3127 men and 2460 women by 800 general practitioners. The
Side Effects of Drugs Annual I0 M.N.G. Dukes, editor 9 Elsevier Science Publishers B.V., 1986
A post-marketing surveillance of practical experience with ketotifen in 8291 patients who completed records every 3 months for 1 year showed by subjective assessment that 70% of the patients found the medication efficacious. There were no unexpected or unacceptable side effects (4c). The results found in this way are almost always too optimistic. There are various reasons: e.g., selection of the patients is made on the basis of their cooperation, so dropouts may disappear without registration; patients do not want to disappoint their doctors. Twenty-five patients with hay fever or allergic rhinitis were treated with 1 mg and 26 patients with 2 mg ketotifen daily in a doubleblind trial against placebo and clemastine. These figures are much higher than in the postmarketing surveillance study reported last year. Perhaps if one looks for drowsiness with this product, one finds it. In the first week 46% of patients taking 2 mg suffered drowsiness and (curiously enough) 65% of those taking 1 mg daily. Thereafter there was a sharp decline so that after 4 weeks there were no differences between the ketotifen groups and the placebo group. The same happened with the incidence of dry mouth (during the first week 39% with I mg and 19% with 2mg) (5c). In a prospective study for oral prophylaxis of bronchial asthma in 19 children (taking 0.04 mg/kg body weight twice a day) the side effects recorded were vomiting in 1, self-limited vertigo in ! and irritability in 1 child. None of these was severe enough to justify withdrawing the drug (6~).
Chapter 17 F.A. Nelemans
138 In a double-blind study 87 patients were given 1 mg ketotifen and 89 patients 0.5 mg ketotifen twice daily. Twenty patients in the 1 mg group showed side effects and 15 in the 0.5 mg group. Drowsiness (14 and 13 patients respectively) was the main side effect. Tiredness (3 and 2), dizziness (2 and 0), pronounced headache (2 and 0), dry mouth (1 and 2) and eruption (2 and 0) were other side effects (7c).
Tranilast (Rizaben) ( SED A-9, 156) Two patients had severe bladder symptoms which could not be relieved by antibiotic treatment. Cystograms showed severe deformity of the bladder. Cystoscopy revealed velvety, ulcerated areas in the bladder mucosa. Histological examination revealed acute and chronic cystitis with mild eosinophilic infiltration in the submucosa. The symptoms of both patients disappeared after discontinuance of the Japanese antiallergic drug, tranilast. Skin tests with the drug and its metabolites were negative (8c), so that there appears to have been a toxic rather than an allergic reaction.
paracetamol, many adverse reactions that were anaphylactoid in nature have been reported. The most common feature was rash; other features reported included angioedema, hypotension and bronchospasm (ilC). Wheal responses to high concentrations of acetylcysteine (20 mg/ml) were significantly greater in reactors. In 2 patients with a positive reaction the effects could be inhibited by prior therapy with the antihistamine, terfenadine. A 'pseudoallergic' reaction on the basis of histamine liberation rather than an immunological etiology is suggested as the mechanism (17c, 13, 14r The prognosis of the anaphylactoid reaction treated with an antihistamine is favorable.
Bromhexine (SEDA-8, 171; SEDA-9, 156)
SEDA-8, 171; SEDA-9, 156)
In 11 patients with the Sjtgren syndrome, bromhexine improved tear secretion in 7 cases and salivary secretion in 4 (orally 3 times per day 16 mg). Three patients had diarrhea, which improved immediately after reduction of the dose (15C). The combination of feprazone and bromhexine (granular) in a group of 20 children (controlled clinical trial vs acetylcysteine) produced no more side effects (3 cases) than would be expected from bromhexine alone (16c).
Aeetylcysteine (SED-8, 172; SEDA-9, 156)
Carlmcisteine
In a multicenter, double-blind, placebocontrolled inter-patient study 61 patients received 200 mg N-acetylcysteine orally 3 times daily and 60 patients a matching placebo for a 3-month trial period (9c). Of the 75 patients randomized to receive N-acetylcysteine, 4 patients were withdrawn because of side effects (epigastric pain, diarrhea, tiredness and skin rash) and a further l 1 patients complained of unwanted effects during the study, including nausea, vomiting, heartburn, dyspepsia, diarrhea and dizziness. Of the 80 patients randomized to receive placebo 5 were withdrawn because of side effects (nausea, vomiting, dyspepsia and drowsiness) and 22 patients complained of unwanted effects (nausea, vomiting, dry mouth, flatulence, diarrhea and constipation). Two patients receiving N-acetylcysteine and 1 receiving placebo complained of chest tightness during the study. In a general practice study in 248 patients approximately the same findings have been reported (10c). Since the introduction in 1979 of intravenous acetylcysteine as an antidote for overdosage of
Forty patients with chronic obstructive airways disease took part in a double-blind trial comparing carbocisteine syrup (250 mg/5 ml) with matching placebo syrup (during 10 weeks). Four patients (1 on active medication and 3 on pl[acebo) were withdrawn. One in the placebo group was withdrawn because of nausea, the other patients on the basis of the clinical signs (infections) (17r
M U C O L Y T I C AGENTS (SED-IO, 295;
Eprazinone A drug eruption with subcorneal pustulation occurred in a male patient (48 years) during treatment with the antitussive and bronchosecretolytic agent, eprazinone (100 mg/d p.o.). Biopsy showed changes as in pustulosis subcornealis, The etiopathogenetic relationship was confirmed by patch test (18c).
Sobrerol Sobrerol (1-methyl:4-(2-hydroxyisopropyl)cyclohex-l,2-en-6-ol) was investigated in 20 children aged 3--12 years in a dosage of 100 mg
Antiallergic and antitussive drugs Chapter 17 orally 3 times a day and compared with Nacetyicysteine (14). The treatment was continued for 7 days. One of the sobreroi patients (suffering vomiting) and 4 of the N-acetylcysteine patients (vomiting in 2, diarrhea in 2) did not complete the treatment (19c). Zipeprol Zipeprol is a new mucolytic agent. It is given orally in a dose of 225-375 mg/d. Of a group of 26 hospitalized patients 2 complained of somnolence, 4 of nausea and 1 of dizziness. It was not necessary to interrupt the treatment (20c). C O U G H REMEDIES (SED-IO, 296; SEDA-9, 156) Clofedanol Clofedanol is a centrally acting cough suppressant with mild local anesthetic properties. In an open clinical study 30 patients suffering from various bronchopulmonary diseases with and without productive cough were treated with the agent for a period of 14 days, 30 drops 3 times daily (total dosage 128 mg/d). Two patients were withdrawn from the study because of tiredness and vomiting. These side effects disappeared immediately after interruption of the therapy (21c). Glaucine Glaucine is a new non-narcotic antitussive agent. The D-isomer of glaucine is an alkaloid from Glauciumflavum Crantz, a species of Papaveraceae. Glaucine was compared with codeine in a double-blind (90 patients) trial. The dose of D,L-glaucine was 30 mg 3 times daily for 7 days, the dose of codeine 30 mg 3 times daily. Both agents were administered as a syrup. In the double-blind trial constipation and nausea were reported by 9 patients on codeine but by no patients on glaucine. In an open trial with glaucine alone (3 times daily 30 mg in capsules for 28 days) mild constipation was reported by 5 patients (22c). MISCELLANEOUS Almitrine bimesilate It is claimed that almitrine bimesilate, used as a respiratory stimulant, opens up new perspectives in the management of chronic bron-
139 chitis and that it provides significant and sustained improvement of gasometric parameters. In a 6-month double-blind study of the agent (50 mg/d) versus placebo no difference in side effects was observed (23 ~, 24~). Densensitization A dialyzed aqueous extract of pollens chemically conjugated to activated sodium alginate (Conjuvac) was compared with a pyridineextracted, alum-precipitated crude extract (Allpyral): 17 Allpyral and 17 Conjuvac patients received an injection every month as maintenance dose (10,000 P N U out of season, 5000 in season) after an introductory period of weekly rising doses from 1 PNU upwards. No serious adverse effects were seen. The Allpyral patients received only about 1/16th of the dose received by Conjuvac patients in the third year, if dosage is redefined in RAST terms. From the therapeutic point of view there was no difference between the 2 preparations (25c). All general practitioners on the Hampshire Family Practitioner Committee register (U.K.) were sent a questionnaire regarding their experience of desensitization and its side effects. Of a total of 695 doctors, 452 did not use desensitization at all, while 20 used more than 20 courses per year. The questionnaire listed 6 currently available preparations: Alavac, Allpyral, Migen, Norisen, Pollinex and SDV. There were no great differences in side effects between the various preparations. The local immediate reaction occurred after less than 10% of the injections in 30% of the patients and in more than 10% of the injections in 4%. The local delayed reaction occurred after less than 10% of the injections in 16% of the patients and in more than 10% of the injections in 2% of the patients. Nine of 176 doctors reported serious bronchospasm for Alavac and 3 cases of anaphylaxis. Eighteen of 181 reported serious bronchospasm for Allpyral and 3 cases of anaphylaxis. For Migen 9 doctors reported serious bronchospasm and 2 cases of anaphylaxis (1 death). Norison gave no cases with serious bronchospasm but 2 of anaphylaxis (33 doctors reporting). Of 251 doctors prescribing Pollinex 8 mentioned serious bronchospasm and 1 anaphylaxis. SDV was prescribed by 237 doctors; 38 mentioned serious bronchospasm and 11 anaphylaxis (29c). Guaimesal A group of 20 patients with acute exacerbations of chronic bronchitis was treated (blind)
140
Chapter 17 F.A. Nelemans
with 5 0 0 m g capsules of guaimesal. Four patients complained of dyspeptic disturbances which did not require the interruption of therapy. N o deterioration in hematopoietic, renal or liver functions was observed (26c).
(12%) for IPG and placebo; these were mild and cleared without treatment (27c).
Iodopropylidene glycerol (iodinated dimers of glycerol)
A total of 2708 observations by 366 doctors on patients taking letosteine ([ethoxycarboxy (methylthio)ethyl]-thiazolidine-4-carboxylic acid) acid) were sent to the manufacturer; 1527 of these forms could be used and 1181 were excluded. In 1451 of 1527 patients no side effects had been recorded. In 76 cases the side effects mentioned were nausea 11, diarrhea 4, gastralgia 46, and others 15. Only in 4 patients (1 nausea, 3 gastralgia) did the therapy have to be stopped (28c). The use of such collections of data remains doubtful.
Iodopropylidene glycerol (IPG; tablets 30 mg, equivalent to 15 mg organically bound iodine) was tested in a double-blind, randomized, multicenter clinical study compared with placebo as adjunctive expectorant therapy in 60 male and female stable, chronic asthmatics on theophylline maintenance. The dosage was 2 tablets to be taken with water 4 times daily for 28 days. The incidence of side effects was similar
Letosteine (Viscotiol) (SED-IO, 296; SEDA-7, 191)
REFERENCES 1. Fischer H (1984) Ergebnisse einer multizentrischen offenen Priifung mit einer fixen Kombination aus Dinatrium Cromoglicum und Reproterol an 1872 Patienten. Pharmakotherapie, 7, 67. 2. Marks Meyer B (1984) Nebulized cromolyn sodium: efficacy and safety. Immunol. Allergy Pract., 6, 130. 3. Brems H, Pauly N, Thomas J (1984) Fenspiride (Pneumorel 80) dans le traitement des affections aiguEs des voies respiratoires. Ars Med., 39, 55. 4. Maclay WP, Crowder D, Spiro S e t al (1984) Post-marketing surveillance: practical experience with ketotifen. Br. Med. J., 288, 91 I. 5. Weathley D (1984) Ketotifen in hay fever and allergic rhinitis. Practitioner, 228, 685. 6. Arif MA, Nizami SQ (1984) Oral prophylaxis of bronchial asthma in children. J. Pak. Med. Assoc., 34, 90. 7. Okuda M (1984) Clinical investigation of ketotifen in perennial allergic rhinitis: a double-blind comparative study of ketotifen and clemastine fumarate. Rhinology, 22, 171. 8. Miura T, Sugawara T, Fukushima S (1984) Antiallergic drug tranilast induced cystitis: a report of two cases. Jpn. Clin. Urol., 38, 891. 9. Jackson IM, Barnes J, Cooksey P (1984) Efficacy and tolerability of oral acetylcysteine (Fabrol) in chronic bronchitis: a double-blind placebo controlled study. J. Int. Med. Res., 12, 198. 10. Tattersall AB, Bridgman KM, Huitson A (1984) Irish general practice study of acetylcysteine (Fabrol) in chronic bronchitis. J. Int. Med. Res., 12, 96. 11. Mant TGK, Tempowski JH, Volans GN et al (1984) Adverse reactions to acetylcysteine and effects of overdose. Br. Med. J., 289, 217. 12. Bateman DN, Woodhouse KW, Rawlins MD (1984) Adverse reactions to N-acetylcysteine. Hum. ToxicoL, 3, 393.
13. Bateman DN, Woodhouse KW, Rawlins MD (1984) Adverse reactions to N-acetylcysteine. Lancet, 8396, 228. 14. Tenebein M (1984) Hypersensitivity-like reactions to N-acetylcysteine. Vet. Hum. Toxicol., 26, Suppl 2, 3. 15. Fossaluzza V (1984) Bromhexin bei der symptomatischen Behandlung des Sj6gren-Syndroms. Klin. Monatsbl. Augenheilkd., 185, 292. 16. Dore A, Forteleoni G, Geromino A et al (1983) Solvelin granulato de angeli (TF 784) nel trattamento delle affezioni broncopolmonari di pertinenza pediatrica. Arch. Med. Intern., 35, 75. 17. Aylward M, Davies DE, Dewland PM (1984) Clinical evaluation of carbocisteine (Mucolex) in the treatment of patients with chronic bronchitis: a double-blind trial with placebo control. Clin. Trials J., 22, 36. ,, 18. Faber M, Maucher OM, Stengel R et al (1984) Eprazinonexanthem mit subkornealer Pustelbildung. Hautarzt, 35, 200. 19. Seidita F, Deiana M, Careddu P (1984) Acute bronchial diseases in paediatrics: therapeutic approach with sobrerol granules. G. Ital. Mal. Torace, 38, 191. 20. Paramelle B (1984) l~tude de l'action fluidifiante du Respil~ne dans le traitement des bronchopneumopathies chroniques. Gaz. Mbd., 91, 86. 21. Cosmi F, Mollaioli M, Aimi M e t al (1983) Attivitfi antitussigena del clofedanolo. Eur. Rev. Med. Pharmacol. Sci., 5, 9. 22. Gastpar H, Criscerolo D, Dieterich HA (1984) Efficacy and tolerability of glaucine as an antitussive agent. Curr. Med. Res. Opin., 9, 21. 23. Saada B (1984) Efficacite clinique et tol6rance du bism~silate d'almitrine darts la bronchite chronique. Sere. Hdp, 60, 1568. 24. Marteau D (I984) Variations de la gazom&rie art6rielle au cours des traitements par le bism~silate
Antiallergic and antitussive drugs
Chapter 17
d'almitrine. Sere. H6p., 60, 1564. 25. Pegelow KO, Belin L, Broman P e t al 0984) Immunotherapy with alginate-conjugated and alum-precipitated grass pollen extracts in patients with allergic rhinoconjunctivitis. Allergy, 39, 275. 26. Ghiringhelli G (1984) Il guaimesal in capsule nel trattamento della bronchite cronica riacutizzata. Clin. Ter., 110, 533. 27. Repsher LH, Glassman JM, Soyka JP 0983) Evaluation of iodopropylidene glycerol as adjunc-
141 tive therapy in stable, chronic asthmatic patients on theophylline maintenance. Today Ther. Trends, 1, 77. 28. Kleisbauer JP (1984) Int6r6t de la mesure du d6bit de pointe dans l'6volution des bronchiteux chroniques: fi propos du suivi de 2708 malades trait6es par Viscotiol. Lyon Mbditerr. Mbd., 22, 8797. 29. Rands DA, Godfrey RC (1983) Side effects of desensitization for allergy - - a general practice survey. J. R. Coll. Gen. Pract., 33, 647.
17
Antiallergic and antitussive drugs
Editorial note Several drugs used in bronchial asthma and cough are dealt with in other chapters. These include xanthine compounds (Chapter 1), the opiates (Chapter 8), sympathomimetic and parasympatholytic agents (Chapter 14), the antihistamines (Chapter 16) and the corticosteroids (Chapter 41).
mean duration of treatment was 8 days and the dosage 2 tablets a day. Clinically, fenspiride was positively appreciated by 9 out of 10 patients. The number of side effects was small and they were not very specific (gastrointestinal, neurovegetative). Less than 10~ of the patients had side effects (3 c)
Ketotifen (Zaditen) (SED-IO, 292; SEDA-8, 171; SEDA-9, 155) DRUGS USED IN B R O N C H I A L ASTHMA
Cromolyn sodium (disodium cromoglieate) (SED-IO, 291; SEDA-8, 170; SEDA-9, 155) The illogical combination of cromolyn sodium with reproterol (SEDA-9, 155) was investigated in a further open multicenter study, now in 1872 patients. Increasing the number of patients does not improve a'basically invalid experiment. Here, too, the patients were pleased with the therapy and the, number of side effects was very small (l c). Since from the start the powdered form of cromoglicate has caused bronchial irritation in very occasional patients, it is interesting to observe the work done with a nebulizer solution. A 1% nebulizer solution (20 mg cromolyn sodium dissolved in 2.5 ml distilled water and nebulized over a 15-min period) has the same therapeutic effect and low incidence of side effects as the substance given by the use of the Spinhaler (20.
Fens#ride (Pneumorel 80) (SED-IO, 296) The efficacy and safety of fenspiride (which has bronchodilator and anti-inflammatory properties) has been studied in 3127 men and 2460 women by 800 general practitioners. The
Side Effects of Drugs Annual I0 M.N.G. Dukes, editor 9 Elsevier Science Publishers B.V., 1986
A post-marketing surveillance of practical experience with ketotifen in 8291 patients who completed records every 3 months for 1 year showed by subjective assessment that 70% of the patients found the medication efficacious. There were no unexpected or unacceptable side effects (4c). The results found in this way are almost always too optimistic. There are various reasons: e.g., selection of the patients is made on the basis of their cooperation, so dropouts may disappear without registration; patients do not want to disappoint their doctors. Twenty-five patients with hay fever or allergic rhinitis were treated with 1 mg and 26 patients with 2 mg ketotifen daily in a doubleblind trial against placebo and clemastine. These figures are much higher than in the postmarketing surveillance study reported last year. Perhaps if one looks for drowsiness with this product, one finds it. In the first week 46% of patients taking 2 mg suffered drowsiness and (curiously enough) 65% of those taking 1 mg daily. Thereafter there was a sharp decline so that after 4 weeks there were no differences between the ketotifen groups and the placebo group. The same happened with the incidence of dry mouth (during the first week 39% with I mg and 19% with 2mg) (5c). In a prospective study for oral prophylaxis of bronchial asthma in 19 children (taking 0.04 mg/kg body weight twice a day) the side effects recorded were vomiting in 1, self-limited vertigo in ! and irritability in 1 child. None of these was severe enough to justify withdrawing the drug (6~).
Chapter 17 F.A. Nelemans
138 In a double-blind study 87 patients were given 1 mg ketotifen and 89 patients 0.5 mg ketotifen twice daily. Twenty patients in the 1 mg group showed side effects and 15 in the 0.5 mg group. Drowsiness (14 and 13 patients respectively) was the main side effect. Tiredness (3 and 2), dizziness (2 and 0), pronounced headache (2 and 0), dry mouth (1 and 2) and eruption (2 and 0) were other side effects (7c).
Tranilast (Rizaben) ( SED A-9, 156) Two patients had severe bladder symptoms which could not be relieved by antibiotic treatment. Cystograms showed severe deformity of the bladder. Cystoscopy revealed velvety, ulcerated areas in the bladder mucosa. Histological examination revealed acute and chronic cystitis with mild eosinophilic infiltration in the submucosa. The symptoms of both patients disappeared after discontinuance of the Japanese antiallergic drug, tranilast. Skin tests with the drug and its metabolites were negative (8c), so that there appears to have been a toxic rather than an allergic reaction.
paracetamol, many adverse reactions that were anaphylactoid in nature have been reported. The most common feature was rash; other features reported included angioedema, hypotension and bronchospasm (ilC). Wheal responses to high concentrations of acetylcysteine (20 mg/ml) were significantly greater in reactors. In 2 patients with a positive reaction the effects could be inhibited by prior therapy with the antihistamine, terfenadine. A 'pseudoallergic' reaction on the basis of histamine liberation rather than an immunological etiology is suggested as the mechanism (17c, 13, 14r The prognosis of the anaphylactoid reaction treated with an antihistamine is favorable.
Bromhexine (SEDA-8, 171; SEDA-9, 156)
SEDA-8, 171; SEDA-9, 156)
In 11 patients with the Sjtgren syndrome, bromhexine improved tear secretion in 7 cases and salivary secretion in 4 (orally 3 times per day 16 mg). Three patients had diarrhea, which improved immediately after reduction of the dose (15C). The combination of feprazone and bromhexine (granular) in a group of 20 children (controlled clinical trial vs acetylcysteine) produced no more side effects (3 cases) than would be expected from bromhexine alone (16c).
Aeetylcysteine (SED-8, 172; SEDA-9, 156)
Carlmcisteine
In a multicenter, double-blind, placebocontrolled inter-patient study 61 patients received 200 mg N-acetylcysteine orally 3 times daily and 60 patients a matching placebo for a 3-month trial period (9c). Of the 75 patients randomized to receive N-acetylcysteine, 4 patients were withdrawn because of side effects (epigastric pain, diarrhea, tiredness and skin rash) and a further l 1 patients complained of unwanted effects during the study, including nausea, vomiting, heartburn, dyspepsia, diarrhea and dizziness. Of the 80 patients randomized to receive placebo 5 were withdrawn because of side effects (nausea, vomiting, dyspepsia and drowsiness) and 22 patients complained of unwanted effects (nausea, vomiting, dry mouth, flatulence, diarrhea and constipation). Two patients receiving N-acetylcysteine and 1 receiving placebo complained of chest tightness during the study. In a general practice study in 248 patients approximately the same findings have been reported (10c). Since the introduction in 1979 of intravenous acetylcysteine as an antidote for overdosage of
Forty patients with chronic obstructive airways disease took part in a double-blind trial comparing carbocisteine syrup (250 mg/5 ml) with matching placebo syrup (during 10 weeks). Four patients (1 on active medication and 3 on pl[acebo) were withdrawn. One in the placebo group was withdrawn because of nausea, the other patients on the basis of the clinical signs (infections) (17r
M U C O L Y T I C AGENTS (SED-IO, 295;
Eprazinone A drug eruption with subcorneal pustulation occurred in a male patient (48 years) during treatment with the antitussive and bronchosecretolytic agent, eprazinone (100 mg/d p.o.). Biopsy showed changes as in pustulosis subcornealis, The etiopathogenetic relationship was confirmed by patch test (18c).
Sobrerol Sobrerol (1-methyl:4-(2-hydroxyisopropyl)cyclohex-l,2-en-6-ol) was investigated in 20 children aged 3--12 years in a dosage of 100 mg
Antiallergic and antitussive drugs Chapter 17 orally 3 times a day and compared with Nacetyicysteine (14). The treatment was continued for 7 days. One of the sobreroi patients (suffering vomiting) and 4 of the N-acetylcysteine patients (vomiting in 2, diarrhea in 2) did not complete the treatment (19c). Zipeprol Zipeprol is a new mucolytic agent. It is given orally in a dose of 225-375 mg/d. Of a group of 26 hospitalized patients 2 complained of somnolence, 4 of nausea and 1 of dizziness. It was not necessary to interrupt the treatment (20c). C O U G H REMEDIES (SED-IO, 296; SEDA-9, 156) Clofedanol Clofedanol is a centrally acting cough suppressant with mild local anesthetic properties. In an open clinical study 30 patients suffering from various bronchopulmonary diseases with and without productive cough were treated with the agent for a period of 14 days, 30 drops 3 times daily (total dosage 128 mg/d). Two patients were withdrawn from the study because of tiredness and vomiting. These side effects disappeared immediately after interruption of the therapy (21c). Glaucine Glaucine is a new non-narcotic antitussive agent. The D-isomer of glaucine is an alkaloid from Glauciumflavum Crantz, a species of Papaveraceae. Glaucine was compared with codeine in a double-blind (90 patients) trial. The dose of D,L-glaucine was 30 mg 3 times daily for 7 days, the dose of codeine 30 mg 3 times daily. Both agents were administered as a syrup. In the double-blind trial constipation and nausea were reported by 9 patients on codeine but by no patients on glaucine. In an open trial with glaucine alone (3 times daily 30 mg in capsules for 28 days) mild constipation was reported by 5 patients (22c). MISCELLANEOUS Almitrine bimesilate It is claimed that almitrine bimesilate, used as a respiratory stimulant, opens up new perspectives in the management of chronic bron-
139 chitis and that it provides significant and sustained improvement of gasometric parameters. In a 6-month double-blind study of the agent (50 mg/d) versus placebo no difference in side effects was observed (23 ~, 24~). Densensitization A dialyzed aqueous extract of pollens chemically conjugated to activated sodium alginate (Conjuvac) was compared with a pyridineextracted, alum-precipitated crude extract (Allpyral): 17 Allpyral and 17 Conjuvac patients received an injection every month as maintenance dose (10,000 P N U out of season, 5000 in season) after an introductory period of weekly rising doses from 1 PNU upwards. No serious adverse effects were seen. The Allpyral patients received only about 1/16th of the dose received by Conjuvac patients in the third year, if dosage is redefined in RAST terms. From the therapeutic point of view there was no difference between the 2 preparations (25c). All general practitioners on the Hampshire Family Practitioner Committee register (U.K.) were sent a questionnaire regarding their experience of desensitization and its side effects. Of a total of 695 doctors, 452 did not use desensitization at all, while 20 used more than 20 courses per year. The questionnaire listed 6 currently available preparations: Alavac, Allpyral, Migen, Norisen, Pollinex and SDV. There were no great differences in side effects between the various preparations. The local immediate reaction occurred after less than 10% of the injections in 30% of the patients and in more than 10% of the injections in 4%. The local delayed reaction occurred after less than 10% of the injections in 16% of the patients and in more than 10% of the injections in 2% of the patients. Nine of 176 doctors reported serious bronchospasm for Alavac and 3 cases of anaphylaxis. Eighteen of 181 reported serious bronchospasm for Allpyral and 3 cases of anaphylaxis. For Migen 9 doctors reported serious bronchospasm and 2 cases of anaphylaxis (1 death). Norison gave no cases with serious bronchospasm but 2 of anaphylaxis (33 doctors reporting). Of 251 doctors prescribing Pollinex 8 mentioned serious bronchospasm and 1 anaphylaxis. SDV was prescribed by 237 doctors; 38 mentioned serious bronchospasm and 11 anaphylaxis (29c). Guaimesal A group of 20 patients with acute exacerbations of chronic bronchitis was treated (blind)
140
Chapter 17 F.A. Nelemans
with 5 0 0 m g capsules of guaimesal. Four patients complained of dyspeptic disturbances which did not require the interruption of therapy. N o deterioration in hematopoietic, renal or liver functions was observed (26c).
(12%) for IPG and placebo; these were mild and cleared without treatment (27c).
Iodopropylidene glycerol (iodinated dimers of glycerol)
A total of 2708 observations by 366 doctors on patients taking letosteine ([ethoxycarboxy (methylthio)ethyl]-thiazolidine-4-carboxylic acid) acid) were sent to the manufacturer; 1527 of these forms could be used and 1181 were excluded. In 1451 of 1527 patients no side effects had been recorded. In 76 cases the side effects mentioned were nausea 11, diarrhea 4, gastralgia 46, and others 15. Only in 4 patients (1 nausea, 3 gastralgia) did the therapy have to be stopped (28c). The use of such collections of data remains doubtful.
Iodopropylidene glycerol (IPG; tablets 30 mg, equivalent to 15 mg organically bound iodine) was tested in a double-blind, randomized, multicenter clinical study compared with placebo as adjunctive expectorant therapy in 60 male and female stable, chronic asthmatics on theophylline maintenance. The dosage was 2 tablets to be taken with water 4 times daily for 28 days. The incidence of side effects was similar
Letosteine (Viscotiol) (SED-IO, 296; SEDA-7, 191)
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Antiallergic and antitussive drugs
Chapter 17
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